title: A Study of Zoledronic Acid as Neo-Adjuvant, Perioperative Therapy in Patients with Resectable Pancreatic Ductal Adenocarcinoma.
abstract: BACKGROUND
  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by abundant granulocytic myeloid-derived suppressor cells (G-MDSC = CD45+/Lin-/CD33+/CD11b+/CD15+), which infiltrate tumors and suppress anti-tumor immunity. We have previously demonstrated in a murine model of PDAC that zoledronic acid (ZA) depletes G-MDSC resulting in decreased tumor growth and improved survival. We report here the results of a phase 1 clinical trial (NCT00892242) using ZA as neo-adjuvant, perioperative therapy in patients with non-metastatic, resectable pancreatic adenocarcinoma.
  
  
  METHODS
  Eligible PDAC patients received ZA (4mg) IV 2 weeks prior to surgery. Patients then received 2 additional doses of ZA 4 weeks apart. Blood and bone marrow were obtained from patients prior to treatment with ZA and 3 months after surgery for analysis of G-MDSC by flow cytometry.
  
  
  RESULTS
  Twenty-three patients received pre-operative ZA with at least 6 months of follow-up Only 15 PDAC patients had non-metastatic PDAC, which was amenable to resection. ZA was well tolerated, and all adverse events were grade 1 or 2. The most common adverse events were fatigue, abdominal pain/discomfort, anorexia, and arthralgia. Of resected PDAC patients treated with ZA, 1- and 2-year overall survival (OS) was 85.7% and 33.3%, respectively, with a median OS of 18 months. This group had a 1- and 2-year progression-free survival (PFS) of 26.9% and 8.9%, respectively, with a median PFS of 12 months. The prevalence of G-MDSC was unchanged in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA.
  
  
  CONCLUSIONS
  ZA is safe and well tolerated as neo-adjuvant, peri-operative therapy in PDAC patients. In this small study, we did not observe a difference in OS or PFS compared to historical controls. Also, there was no difference in the prevalence of G-MDSC in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA.
authors.affiliation: Department of Surgery, Washington University - School of Medicine.
authors.forename: Dominic E
authors.initials: DE
authors.lastname: Sanford
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Porembka
authors.forename: Roheena Z
authors.initials: RZ
authors.lastname: Panni
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Mitchem
authors.forename: Brian A
authors.initials: BA
authors.lastname: Belt
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Plambeck-Suess
authors.forename: Goldie
authors.initials: G
authors.lastname: Lin
authors.forename: David G
authors.initials: DG
authors.lastname: Denardo
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Fields
authors.forename: William G
authors.initials: WG
authors.lastname: Hawkins
authors.forename: Steven M
authors.initials: SM
authors.lastname: Strasberg
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.forename: Simon Peter
authors.initials: SP
authors.lastname: Goedegebuure
authors.forename: David C
authors.initials: DC
authors.lastname: Linehan